Use of anti-aging glycoprotein for enhancing survival of neurosensory precursor cells

ABSTRACT

The present disclosure relates to an in vitro method for enhancing engraftment of neurosensory precursor cell comprising the step of contacting an isolated neurosensory precursor cell prior to a transplantation in a subject in need thereof, with a gem-difluorinated C-glycopeptide compound of general formula I, or a pharmaceutically acceptable base, addition salt with an acid, hydrate or solvate thereof:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/073,282, which is a U.S. National Phase application under 35 USC §371 of PCT/IB2017/050444, filed Jan. 27, 2017, which claims priorityfrom and the benefit of U.S. Provisional Patent Application No.62/287,857, filed Jan. 27, 2016, the specifications of all of the aboveare hereby incorporated by reference in their entireties.

BACKGROUND (a) Field

The subject matter disclosed generally relates to in vitro method forenhancing engraftment of neurosensory precursor cells and in vitromethods for protecting isolated neurosensory precursor cells fromprostaglandin E2 toxicity.

(b) Related Prior Art

Cell transplantation is a promising approach to replace tissue lost as aconsequence of retinal degenerative diseases. For example, specializedNPCs such as retinal precursor cells are being investigated for use inretinal diseases such as age-related macular degeneration (AMD) andretinitis pigmentosa (RP) (Klassen, 2015). However, it has becomeevident that the survival and functional integration rate oftransplanted NPCs and in particular specialized retinal precursor cells,remains low (1-3% and 3.5%, respectively; Stone et al., 2013 andWarre-Cornish et al., 2014). The factors that inhibit transplanted cellengraftment remain largely unknown, in part because many adverse factorscould be at play during in vivo experiments. These factors includeimmune-rejection, sub-optimal type of NPC, trauma during cell delivery,nutritional deficits in the target tissue and toxic compounds secretedfrom the target tissue (Ma et al., 2011; West et al., 2012; Singh etal., 2013). To highlight one factor, many neurodegenerative tissuesundergo necrosis and as such release toxic metabolites such as theby-products of phospholipids released by the porous plasma membrane(e.g. prostaglandins; Ricciotti and FitzGerald, 2011), free nucleicacids (Cavassani et al., 2008) and high mobility group box 1 protein(HMGB1; Scaffidi et al., 2002). The release of such toxic factors is ofparticular concern as it triggers inflammatory signals which ultimatelylead to more cell death (Zhou and Yuan, 2014). Although numerous factorsare released from necrotic tissues, prostaglandins and specificallyprostaglandin E2 (PGE2) has been shown to stimulate cell death inseveral cell culture systems. It has been suggested that duringnecrosis, as cell walls break down, membrane-derived arachidonic acid isreleased. This occurs with upregulation of the enzyme cyclooxygenase-2(COX-2) triggered by cell death signalling and leads to the conversionof arachidonic acid to PGE2 (e.g., Ricciotti and FitzGerald, 2011;Takadera et al., 2004 and Miyagishi et al., 2013).

A recently characterized anti-aging glycopeptide (AAGP™) as a potentialprotective agent, is a small, stable, synthetic analog of anti-freezeprotein (AFP). AFP has been shown to protect cells against extremeconditions has been shown to protect cells for example, against exposureto extreme temperatures and ultraviolet irradiation. AAGP™ compounds aregem difluorinated C-glycopeptides which have also been proposed to haveapplicability under harsh cellular stresses, such as nutrientdeprivation, high temperature and cryopreservation, oxidative stressfrom hydrogen peroxide (H₂O₂), UV irradiation, and inflammation. Thecytoprotective effect of this AAGP™ compound is tested in isolated NPC.

Therefore, there exists a need in the art for means of improvingtransplanted NPC engraftment.

SUMMARY

According to an embodiment, there is provided an in vitro method forenhancing engraftment of neurosensory precursor cells comprising thestep of:

-   -   a) contacting an isolated neurosensory precursor cell prior to a        transplantation in a subject in need thereof, with a        gem-difluorinated C-glycopeptide compound of general formula I,        or a pharmaceutically acceptable base, addition salt with an        acid, hydrate or solvate thereof, and then washing the isolated        neurosensory precursor cells to remove the compound:

in which:

-   -   N is an integer between 1 and 5,    -   R⁴═H, AA₁, or AA₁-AA₂,    -   R⁵═OH, AA₁, or AA₁-AA₂,    -   AA₁ and AA₂ independently represent amino acids with a non-polar        side chain and    -   R¹, R², R³ are independent groups in which two of R¹, R² and R³        are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or        CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

-   -   in which:        -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which            GP is a protector group selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁷′OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl,        or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function.

According to another embodiment, there is provided an in vitro methodfor protecting isolated neurosensory precursor cells from prostaglandinE2 toxicity comprising the step of:

-   -   a) contacting an isolated neurosensory precursor cells with a        gem-difluorinated C-glycopeptide compound of general formula I,        or a pharmaceutically acceptable base, addition salt with an        acid, hydrate or solvate thereof, and then washing the isolated        neurosensory cells to remove the compound:

in which:

-   -   N is an integer between 1 and 5,    -   R⁴═H, AA₁, or AA₁-AA₂,    -   R⁵═OH, AA₁, or AA₁-AA₂,    -   AA₁ and AA₂ independently represent amino acids with a non-polar        side chain and    -   R¹, R², R³ are independent groups in which two of R¹, R² and R³        are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or        CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

-   -   in which:        -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which            GP is a protector group selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then R³=

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl,        or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function        wherein the compound protects the isolated neurosensory        precursor cells from prostaglandin E2 toxicity.

The contacting may be prior to a transplantation in a subject in needthereof.

The compound of formula I may be a compound of formula II:

-   -   in which: N is an integer between 1 and 5,        -   and        -   R¹, R², R³ are independent groups in which two of R¹, R² and            R³ are selected from H, CH₃ and the remaining R¹, R² and R³            is

-   -   in which: n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″ or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl, or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a            protector group selected from alkyl, benzyl, trimethylsilyl,            tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate            group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H or CH₃,

-   then

in which: n is an integer between 3 and 4,

-   -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or        -   C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H or CH₃,

-   then

in which: n is an integer between 3 and 4,

-   -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl,        -   Bn, tosylate, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H or CH₃,

-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,-   R⁸ is a hydrogen atom or a free or protected alcohol function.

The compound of formula I may be a compound of formula III:

(III).

The isolated neurosensory precursor cell may be contacted with thecompound for at least 1 hour.

The concentration of the compound may be from about 1 mg/ml to about 5mg/ml.

The concentration of the compound may be from about 1 mg/ml to about 3mg/ml, or from about 3 mg/ml to about 5 mg/ml.

The isolated neurosensory precursor cell may be a photoreceptorprecursor cell.

According to another embodiment, there is provided an isolatedneurosensory precursor cell prepared according to the method of thepresent inventon.

According to another embodiment, there is provided a method oftransplanting isolated neurosensory precursor cell in a subject in needthereof comprising the steps of

-   -   a) transplanting an isolated isolated neurosensory precursor        cell prepared according to the method of the present invention,        in the subject in need thereof.

The method may further comprise the step of:

-   -   b) transplanting the treated isolated neurosensory precursor        cell from step a) in the subject in need thereof, wherein the        subject may be receiving an immunosuppressant drug.

The immunosuppressant drug may be daclizumab, sirolimus, tacrolimus,cyclosporine, or a combination thereof.

The subject may be a human subject.

According to another embodiment, there is provided a method of treatinga retinal degenerative disease comprising the step of:

-   -   a) transplanting an isolated neurosensory precursor cell        prepared according to the method of the present invention in the        subject in need thereof.

The retinal degenerative disease may be age-related macular degeneration(AMD), retinitis pigmentosa (RP), retinal vasculitis, or sarcoidosis.

According to another embodiment, there is provided a use of an isolatedneurosensory precursor cell prepared according to the method of thepresent invention, for transplantation to a subject in need thereof.

According to another embodiment, there is provided a use of an isolatedneurosensory precursor cell prepared according to the method of thepresent invention, for treatment of a retinal degenerative disease in asubject in need thereof.

The retinal degenerative disease may be age-related macular degeneration(AMD), retinitis pigmentosa (RP), retinal vasculitis, or sarcoidosis.

According to another embodiment, there is provided an isolatedneurosensory precursor cell according to the method of the presentinvention, for transplantation to a subject in need thereof.

The isolated neurosensory precursor cell may be a photoreceptorprecursor cell.

According to another embodiment, there is provided an isolatedneurosensory precursor cell contacted with a gem-difluorinatedC-glycopeptide compound of general formula I, or a pharmaceuticallyacceptable base, addition salt with an acid, hydrate or solvate thereof:

in which:

-   -   N is an integer between 1 and 5,    -   R⁴═H, AA₁, or AA₁-AA₂,    -   R⁵═OH, AA₁, or AA₁-AA₂,    -   AA₁ and AA₂ independently represent amino acids with a non-polar        side chain and    -   R¹, R², R³ are independent groups in which two of R¹, R² and R³        are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or        CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

-   -   in which:        -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which            GP is a protector group selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl,        or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function.

The compound of formula I may be a compound of formula II:

-   -   in which: N is an integer between 1 and 5,        -   and        -   R¹, R², R³ are independent groups in which two of R¹, R² and            R³ are selected from H, CH₃ and the remaining R¹, R² and R³            is

-   -   in which: n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″ or SR′″,            -   where R═H, benzyl, trimethylsilyl,                tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or                acetate group,            -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate                group, C(═O)-alkyl, or C(═O)-Bn,            -   R′″═H, alkyl, or acetate group,        -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a            protector group selected from alkyl, benzyl, trimethylsilyl,            tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate            group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H or CH₃,

-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group,        -   C(═O)-alkyl, or        -   C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R¹═R³═H or CH₃,-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl,        -   Bn, tosylate, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,    -   if R²═R³═H or CH₃,-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,-   R⁸ is a hydrogen atom or a free or protected alcohol function.

The compound of formula I may be a compound of formula III:

The isolated neurosensory precursor cell may be contacted with fromabout from about 0.01 mg/ml to about 5 mg/ml of the compound of formulaI, formula II or formula III.

The isolated neurosensory precursor cell may be contacted with fromabout from about 1 mg/ml to about 5 mg/ml, or from about 1 mg/ml toabout 3 mg/ml, or from about 3 mg/ml to about 5 mg/ml of the compound offormula I, formula II or formula III.

The isolated neurosensory precursor cell may be contacted with thecompound for at least 1 hour.

The isolated neurosensory precursor cell may be washed to remove thecompound of formula I, II or III.

The isolated neurosensory precursor cell may be a photoreceptorprecursor cell.

According to another embodiment, there may be provided a use of agem-difluorinated C-glycopeptide compound of general formula I, or apharmaceutically acceptable base, addition salt with an acid, hydrate orsolvate thereof, for enhancing engraftment of isolated neurosensoryprecursor cell in a subject in need thereof:

in which:

-   -   N is an integer between 1 and 5,    -   R⁴═H, AA₁, or AA₁-AA₂,    -   R⁵═OH, AA₁, or AA₁-AA₂,    -   AA₁ and AA₂ independently represent amino acids with a non-polar        side chain and    -   R¹, R², R³ are independent groups in which two of R¹, R² and R³        are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or        CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

-   -   in which:        -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which            GP is a protector group selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl,        or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function.

According to another embodiment, there is provided an use of agem-difluorinated C-glycopeptide compound of general formula I, or apharmaceutically acceptable base, addition salt with an acid, hydrate orsolvate thereof, for protecting isolated neurosensory precursor cellfrom prostaglandin E2 toxicity prior to transplantation in a subject inneed thereof:

in which:

-   -   N is an integer between 1 and 5,    -   R⁴═H, AA₁, or AA₁-AA₂,    -   R⁵═OH, AA₁, or AA₁-AA₂,    -   AA₁ and AA₂ independently represent amino acids with a non-polar        side chain and    -   R1_(,) R2, R³ are independent groups in which two of R¹, R² and        R³ are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or        CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

-   -   in which:        -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which            GP is a protector group selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl,        or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function.

The subject may be a human subject.

The isolated neurosensory precursor cell may be a photoreceptorprecursor cell.

The compound of formula I may be a compound of formula II:

-   -   in which: N is an integer between 1 and 5,        -   and        -   R¹, R², R³ are independent groups in which two of R¹, R² and            R³ are selected from H, CH₃ and the remaining R¹, R² and R³            is

-   -   in which: n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″ or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl, or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a            protector group selected from alkyl, benzyl, trimethylsilyl,            tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate            group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H or CH₃,

-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group,        -   C(═O)-alkyl, or        -   C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R¹═R³═H or CH₃,-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl,        -   Bn, tosylate, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R²═R³═H or CH₃,-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,-   R⁸ is a hydrogen atom or a free or protected alcohol function.

The compound of formula I may be a compound of formula III:

The isolated neurosensory precursor cell may be contacted with fromabout from about 0.01 mg/ml to about 5 mg/ml of the compound of formulaI, formula II or formula III.

The isolated neurosensory precursor cell may be contacted with fromabout from about 1 mg/ml to about 5 mg/ml, or from about 1 mg/ml toabout 3 mg/ml, or from about 3 mg/ml to about 5 mg/ml of the compound offormula I, formula II or formula III.

The isolated neurosensory precursor cell may be contacted with thecompound for at least 1 hour.

The isolated neurosensory precursor cell may be washed to remove thecompound of formula I, II or III.

The isolated neurosensory precursor cell may be a photoreceptorprecursor cell.

The use may be for the treatment of a retinal degenerative disease in asubject in need thereof.

The retinal degenerative disease may be age-related macular degeneration(AMD), retinitis pigmentosa (RP), retinal vasculitis, or sarcoidosis.

According to another embodiment, there is provided an gem-difluorinatedC-glycopeptide compound of general formula I, or a pharmaceuticallyacceptable base, addition salt with an acid, hydrate or solvate thereof,for use in enhancing engraftment of an isolated neurosensory precursorcell in a subject in need thereof:

in which:

-   -   N is an integer between 1 and 5,    -   R⁴═H, AA₁, or AA₁-AA₂,    -   R⁵═OH, AA₁, or AA₁-AA₂,    -   AA₁ and AA₂ independently represent amino acids with a non-polar        side chain and    -   R¹, R², R³ are independent groups in which two of R¹, R² and R³        are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or        CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

-   -   in which:        -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which            GP is a protector group selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl,        or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function.

According to another embodiment, there is provided an gem-difluorinatedC-glycopeptide compound of general formula I, or a pharmaceuticallyacceptable base, addition salt with an acid, hydrate or solvate thereof,for protecting isolated neurosensory precursor cell from prostaglandinE2 toxicity prior to transplantation in a subject in need thereof:

in which:

-   -   N is an integer between 1 and 5,    -   R⁴═H, AA₁, or AA₁-AA₂,    -   R⁵═OH, AA₁, or AA₁-AA₂,    -   AA₁ and AA₂ independently represent amino acids with a non-polar        side chain and    -   R¹, R², R³ are independent groups in which two of R¹, R² and R³        are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or        CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

-   -   in which:        -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which            GP is a protector group selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl,        or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,

-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃

-   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP        is a protector group selected from alkyl, benzyl,        trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function.

The subject may be a human subject.

The compound of formula I may be a compound of formula II:

-   -   in which: N is an integer between 1 and 5,        -   and        -   R¹, R², R³ are independent groups in which two of R¹, R² and            R³ are selected from H, CH₃ and the remaining R¹, R² and R³            is

-   -   in which: n is an integer between 3 and 4,        -   Y, Y′ are independent groups            -   in which Y, Y′═H, OR, N₃, NR′R″ or SR′″,                -   where R═H, benzyl, trimethylsilyl,                    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or                    acetate group,                -   R′, R″ independently=H, alkyl, allyl, benzyl,                    tosylate group, C(═O)-alkyl, or C(═O)-Bn,                -   R′″═H, alkyl, or acetate group,        -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a            protector group selected from alkyl, benzyl, trimethylsilyl,            tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate            group,        -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″            are independently selected from alkyl, benzyl,            trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl or acetate group,        -   R⁸ is a hydrogen atom H or a free or protected alcohol            function,            and

-   if R¹═R²═H or CH₃,

-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group,        -   C(═O)-alkyl, or        -   C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R¹═R³═H or CH₃,-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′═H, OR, N₃, NR′R″, SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl,        -   Bn, tosylate, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R²═R³═H or CH₃,-   then

-   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups        -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,        -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,            tert-butyldiphenylsilyl, or acetate group,        -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate            group, C(═O)-alkyl, or C(═O)-Bn,        -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,-   R⁸ is a hydrogen atom or a free or protected alcohol function.

The compound of formula I may be a compound of formula III:

The contacting the isolated neurosensory precursor cells may be withfrom about from about 0.01 mg/ml to about 5 mg/ml, or from about 1 mg/mlto about 3 mg/ml, or from about 3 mg/ml to about 5 mg/ml of the compoundof formula I, formula II or formula III.

The compound of formula I, II or III may be washed away to be removefrom the isolated neurosensory precursor cell.

The the compound of formula I, II or III may be in contact with theisolated neurosensory precursor cell may be contacted for at least 1hour. The following terms are defined below.

The isolated neurosensory precursor cell may be a photoreceptorprecursor cell.

The term «composition» as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition or other compositions in general,is intended to encompass a product comprising the active ingredient(s)and the inert ingredient(s) that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions or other compositions ingeneral of the present invention encompass any composition made byadmixing a compound of the present invention and a pharmaceuticallyacceptable carrier. By “pharmaceutically acceptable” or “acceptable” itis meant the carrier, diluent or excipient must be compatible with theother ingredients of the formulation and not deleterious to therecipient thereof.

The terms “neurosensory precursor cell”, are intended to mean cellsderived from human embryonic stem cells or induced pluripotent stemcells, isolated through known protocols and/or as described hereinbelow, as well as cells of grown in vivo, ex vivo and/or in vitro.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. Where the specified number of carbon atoms permits, e.g., fromC3-10, the term alkyl also includes cycloalkyl groups, and combinationsof linear or branched alkyl chains combined with cycloalkyl structures.When no number of carbon atoms is specified, C1-6 is intended.

“Cycloalkyl” is a subset of alkyl and means a saturated carbocyclic ringhaving a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like. A cycloalkyl group generally is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C1-6 alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C1-6 alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C1-6 alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C1-6alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂ ⁻), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkylsulfinyl” refers to straight or branched chainalkylsulfoxides of the number of carbon atoms specified (e.g., C1-6alkylsulfinyl), or any number within this range [i.e., methylsulfinyl(MeSO—), ethylsulfinyl, isopropylsulfinyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO⁻), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

“Heterocyclyl” refer to saturated or unsaturated non-aromatic rings orring systems containing at least one heteroatom selected from O, S andN, further including the oxidized forms of sulfur, namely SO and SO₂.Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran,1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine,1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine,tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane,1,3-dithiane, oxathiane, thiomorpholine, 2-oxopiperidin-1-yl,2-oxopyrrolidin-1-yl, 2-oxoazetidin-1-yl,1,2,4-oxadiazin-5(6H)-one-3-yl, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls thus include heteroaryls fused to other kinds of rings, suchas aryls, cycloalkyls and heterocycles that are not aromatic. Examplesof heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridyl, oxazolyl, oxadiazolyl (in particular,1,3,4-oxadiazol-2-yl and 1,2,4-oxadiazol-3-yl), thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl,benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl,dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl,quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl,purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl,benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and thelike. For heterocyclyl and heteroaryl groups, rings and ring systemscontaining from 3-15 atoms are included, forming 1-3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃O andCF₃CH₂O).

Before describing the present invention in detail, a number of termswill be defined. As used herein, the singular forms “a”, “an”, and “the”include plural referents unless the context clearly dictates otherwise.

It is noted that terms like “preferably”, “commonly”, and “typically”are not utilized herein to limit the scope of the claimed invention orto imply that certain features are critical, essential, or evenimportant to the structure or function of the claimed invention. Rather,these terms are merely intended to highlight alternative or additionalfeatures that can or cannot be utilized in a particular embodiment ofthe present invention.

For the purposes of describing and defining the present invention it isnoted that the term “substantially” is utilized herein to represent theinherent degree of uncertainty that can be attributed to anyquantitative comparison, value, measurement, or other representation.The term “substantially” is also utilized herein to represent the degreeby which a quantitative representation can vary from a stated referencewithout resulting in a change in the basic function of the subjectmatter at issue.

Features and advantages of the subject matter hereof will become moreapparent in light of the following detailed description of selectedembodiments, as illustrated in the accompanying figures. As will berealized, the subject matter disclosed and claimed is capable ofmodifications in various respects, all without departing from the scopeof the claims. Accordingly, the drawings and the description are to beregarded as illustrative in nature, and not as restrictive and the fullscope of the subject matter is set forth in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the present disclosure will becomeapparent from the following detailed description, taken in combinationwith the appended drawings, in which:

FIGS. 1A-1B illustrate the ex vivo model system as used to identify thepresent invention. (FIG. 1A) Schematic representation of the co-culturemodel system. Retinal pigment epithelium (RPE) is cultured on apolyester membrane and a neurosensory retinal explant is placed upon itwith a tissue culture insert (polytetrafluoroethylene membrane). Thephotoreceptor layer faces the apical surface of the RPE. Precursor cellsare placed upon the RPE surface before the retinal explant is added tothe culture. (FIG. 1B) A low magnification representative image of afrozen cross-section through the co-culture model system. The precursorcells (arrowheads) reside on top of the RPE layer and underneath theretinal explant.

FIGS. 2A-2C illustrates that AAGP™ reduces the amount of prostaglandinE2 (PGE2) secreted by degenerating explants and the level of COX-2expression. PGE2 is toxic to photoreceptor precursor cells (PPCs). (FIG.2A) Rat retinal explants were cultured in explant medium with or without4 mg/ml AAGP (n=3 for each condition). Explant media was replaced after24 hours and replenished every other day with medium not containingAAGP. After ten days, explant medium was collected and processed forPGE2 ELISA. Histograms represent the amount of PGE2 (pg/ml) present inthe explant medium. (FIG. 2B) COX-2 expression was assessed by RT-qPCRin stressed ARPE-19 cells in the presence or absence of 4 mg/ml AAGP(n=4). Histograms represent fold change in COX-2 expression, normalizedto GAPDH. (FIG. 2C) Cultured PPCs were treated with increasing amountsof PGE2 for 48 hours, followed by the MTT assay (n=4). The effect onPPCs' metabolic activity was plotted as a function of PGE2concentrations.

FIG. 3 illustrates that Cell survival is enhanced by pre-incubation withAAGP™. Untreated or AAGP™-treated PPCs are fluorescently labelled andplaced between retinal explants and RPE for ten days (n=4). Live PPCsare separated by Fluorescence-Activated Cell Sorting and the proportionof cells surviving after 10 days of co-culture was calculated. Percentcell survival of untreated and AAGP-treated PPCs was plotted (

) and for each condition the average±SEM is represented by a thick blackline.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In embodiments there are disclosed an in vitro method for enhancingengraftment of neurosensory precursor cells comprising the step of:

-   a) contacting an isolated neurosensory precursor cell prior to a    transplantation in a subject in need thereof, with a    gem-difluorinated C-glycopeptide compound of general formula I, or a    pharmaceutically acceptable base, addition salt with an acid,    hydrate or solvate thereof, and then washing the isolated    neurosensory precursor cells to remove the compound:

-   in which:    -   N is an integer between 1 and 5,-   R⁴═H, AA₁, or AA₁-AA₂,-   R⁵═OH, AA₁, or AA₁-AA₂,-   AA₁ and AA₂ independently represent amino acids with a non-polar    side chain-   and-   R¹, R², R³ are independent groups in which two of R¹, R² and R³ are    selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or CH(CH₃)CH₂CH₃    and the remaining R¹, R², R³ is

-   in which:    -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups-   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which GP is a    protector group selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   and-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃-   then

-   in which: n is an integer between 3 and 4,-   Y, Y′ are independent groups    -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl, or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl, or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is    a protector group selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃-   then

-   in which: n is an integer between 3 and 4,-   Y, Y′ are independent groups-   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl, or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl, or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is    a protector group selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃-   then

-   in which: n is an integer between 3 and 4,-   Y, Y′ are independent groups-   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl, or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl, or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is    a protector group selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl,-   tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function.

In another embodiments there is disclosed an in vitro method forprotecting isolated neurosensory precursor cells from prostaglandin E2toxicity comprising the step of:

-   a) contacting an isolated neurosensory precursor cells with a    gem-difluorinated C-glycopeptide compound of general formula I, or a    pharmaceutically acceptable base, addition salt with an acid,    hydrate or solvate thereof, and then washing the isolated    neurosensory cells to remove the compound:

-   in which:    -   N is an integer between 1 and 5,-   R⁴═H, AA₁, or AA₁-AA₂,-   R⁵═OH, AA₁, or AA₁-AA₂,-   AA₁ and AA₂ independently represent amino acids with a non-polar    side chain-   and-   R¹, R², R³ are independent groups in which two of R¹, R² and R³ are    selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂ or CH(CH₃)CH₂CH₃    and the remaining R¹, R², R³ is

-   in which:    -   n is an integer between 3 and 4,        -   Y, Y′ are independent groups-   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which GP is a    protector group selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   and-   if R¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃-   then

-   in which: n is an integer between 3 and 4,-   Y, Y′ are independent groups    -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl, or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl, or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is    a protector group selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R¹═R³═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃-   then

-   in which: n is an integer between 3 and 4,-   Y, Y′ are independent groups-   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl, or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl, or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is    a protector group selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function,-   if R²═R³═H, CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃-   then

-   in which: n is an integer between 3 and 4,-   Y, Y′ are independent groups-   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,-   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,    tert-butyldiphenylsilyl, or acetate group,-   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,    C(═O)-alkyl, or C(═O)-Bn,-   R′″═H, alkyl, or acetate group,-   R⁶ is H, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is    a protector group selected from alkyl, benzyl, trimethylsilyl,    tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,-   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are    independently selected from alkyl, benzyl, trimethylsilyl,    tertbutyldimethylsilyl,-   tert-butyldiphenylsilyl, or acetate group,-   R⁸ is a hydrogen atom H or a free or protected alcohol function-   wherein the compound protects the isolated neurosensory precursor    cells from prostaglandin E2 toxicity.

Contacting may be prior to a transplantation in a subject in needthereof, for example, a human subject.

In embodiments, the compound of formula I is a compound of formula II:

-   -   in which: N is an integer between 1 and 5,    -   and    -   R¹, R², R³ are independent groups in which two of R¹, R² and R³        are selected from H, CH₃ and the remaining R¹, R² and R³ is

-   -   in which: n is an integer between 3 and 4,        -   Y, Y′ are independent groups    -   in which Y, Y′═H, OR, N₃, NR′R″ or SR′″,    -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,        C(═O)-alkyl, or C(═O)-Bn,    -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,    -   and    -   if R¹═R²═H or CH₃,    -   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups    -   in which Y, Y′═H, OR, N₃, NR′R″, or SR′″,    -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,        C(═O)-alkyl, or    -   C(═O)-Bn,    -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,    -   if R¹═R³═H or CH₃,    -   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups    -   in which Y, Y′═H, OR, N₃, NR′R″, SR′″, 1

where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group,

-   -   R′, R″ independently=H, alkyl, allyl,    -   Bn, tosylate, C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate        group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom H or a free or protected alcohol function,    -   if R²═R³═H or CH₃,    -   then

-   -   in which: n is an integer between 3 and 4,    -   Y, Y′ are independent groups    -   in which Y, Y′H, OR, N₃, NR′R″, or SR′″,    -   where R═H, benzyl, trimethylsilyl, tert-butyldimethylsilyl,        tert-butyldiphenylsilyl, or acetate group,    -   R′, R″ independently=H, alkyl, allyl, benzyl, tosylate group,        C(═O)-alkyl, or C(═O)-Bn,    -   R′″═H, alkyl, or acetate group,    -   R⁶ is selected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a        protector group selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ are        independently selected from alkyl, benzyl, trimethylsilyl,        tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate        group,    -   R⁸ is a hydrogen atom or a free or protected alcohol function.

In an embodiment, the compound of formula I is a compound of formulaIII:

Contacting the isolated neurosensory precursor cells is with from aboutfrom about 0.01 mg/ml to about 5 mg/ml, or about 1 mg/ml to about 5mg/ml, or 1 mg/ml to about 3 mg/ml, or from about 3 mg/ml to about 5mg/ml of the compound of formula I, formula II or formula III.

According to another embodiment, there is disclosed an isolatedneurosensory precursor cells prepared according to the method of thepresent invention.

According to another embodiment, there is disclosed a method oftransplanting neurosensory precursor cells in a subject in need thereofcomprising the steps of:

-   -   a) transplanting an isolated neurosensory precursor cells        prepared according to the method of the present invention, in        the subject in need thereof.

According to another embodiment, there is disclosed a method of treatinga retinal degenerative disease comprising the step of:

-   -   a) transplanting an isolated neurosensory precursor cell        prepared according to the method of the present invention, in        the subject in need thereof.

In embodiments, the immunosuppressant drug may be daclizumab, sirolimus,tacrolimus, cyclosporine, or a combination thereof.

According to another embodiment, there is disclosed a method of treatinga retinal degenerative disease comprising the step of:

-   -   a) transplanting an isolated neurosensory precursor cell        prepared according to the method of the present invention, in        the subject in need thereof.

The retinal degenerative disease may be age-related macular degeneration(AMD), retinitis pigmentosa (RP), retinal vasculitis, or sarcoidosis.

According to another embodiment, there is provided a use of an isolatedneurosensory precursor cell prepared according to the method of thepresent invention, for transplantation to a subject in need thereof.

According to another embodiment, there is provided a use of an isolatedneurosensory precursor cell prepared according to the method of thepresent invention, for treatment of a retinal degenerative disease in asubject in need thereof.

The retinal degenerative disease is age-related macular degeneration(AMD), retinitis pigmentosa (RP), retinal vasculitis, or sarcoidosis.

According to another embodiment, there is provided a use of an isolatedneurosensory precursor cell according to the method of the presentinvention, for transplantation to a subject in need thereof.

According to another embodiment, there is provided an isolatedneurosensory precursor cell contacted with a gem-difluorinatedC-glycopeptide compound of general formula I (above), or apharmaceutically acceptable base, addition salt with an acid, hydrate orsolvate thereof. The compound of formula I may be a compound of formulaII (as shown above). The compound of formula I may be a compound offormula III (as shown above).

According to another embodiment, there is provided a use of agem-difluorinated C-glycopeptide compound of general formula I (as shownabove), or a pharmaceutically acceptable base, addition salt with anacid, hydrate or solvate thereof, for enhancing engraftment of isolatedneurosensory precursor cell in a subject in need thereof.

According to another embodiment, there is provided a use of agem-difluorinated C-glycopeptide compound of general formula I (as shownabove), or a pharmaceutically acceptable base, addition salt with anacid, hydrate or solvate thereof, for protecting isolated neurosensoryprecursor cell from prostaglandin E2 toxicity prior to transplantationin a subject in need thereof. The formula I may be a compound of formulaII (as shown above). The compound of formula I may be a compound offormula III as shown above.

According to another embodiment, there is provided a gem-difluorinatedC-glycopeptide compound of general formula I (as shown above), or apharmaceutically acceptable base, addition salt with an acid, hydrate orsolvate thereof, for use in enhancing engraftment of an isolatedneurosensory precursor cell in a subject in need thereof. The formula Imay be a compound of formula II (as shown above). The compound offormula I may be a compound of formula III as shown above.

According to another embodiment, there is provided a gem-difluorinatedC-glycopeptide compound of general formula I, or a pharmaceuticallyacceptable base, addition salt with an acid, hydrate or solvate thereof,for protecting isolated neurosensory precursor cell from prostaglandinE2 toxicity prior to transplantation in a subject in need thereof. Theformula I may be a compound of formula II (as shown above). The compoundof formula I may be a compound of formula III as shown above. Thecompound of formula I, II or III may be washed away to be remove fromthe isolated neurosensory precursor cell.

The invention includes the compounds as shown, and also includes (wherepossible) individual diastereomers, enantiomers, and epimers of thecompounds, and mixtures of diastereomers and/or enantiomers thereofincluding racemic mixtures. Although the specific stereochemistriesdisclosed herein are preferred, other stereoisomers, includingdiastereomers, enantiomers, epimers, and mixtures of these may also beuseful. Inactive or less active diastereoisomers and enantiomers areuseful for scientific studies relating to the targets and/or themechanism of activation.

The compounds disclosed herein may be used in pharmaceuticalcompositions comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds may be used in pharmaceutical compositions that includeone or more other active pharmaceutical ingredients. The compounds mayalso be used in pharmaceutical compositions in which the compound ofFormula I, II or III, or a pharmaceutically acceptable salt thereof isthe only active ingredient.

Compounds of structural Formula I, structural Formula II and/orstructural Formula III may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of structural Formula I, structural Formula II and/orstructural Formula III.

Compounds of structural Formula I, structural Formula II and/orstructural Formula III may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration.

Alternatively, any stereoisomer of a compound of the general structuralFormula I, structural Formula II and/or structural Formula III may beobtained by stereospecific synthesis using optically pure startingmaterials or reagents of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention.

In the compounds of generic Formula I, Formula II and/or Formula III,the atoms may exhibit their natural isotopic abundances, or one or moreof the atoms may be artificially enriched in a particular isotope havingthe same atomic number, but an atomic mass or mass number different fromthe atomic mass or mass number predominantly found in nature. Thepresent invention is meant to include all suitable isotopic variationsof the compounds of generic Formula I, Formula II and/or Formula III.For example, different isotopic forms of hydrogen (H) include protium(¹H) and deuterium (²H). Protium is the predominant hydrogen isotopefound in nature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundswithin generic Formula I, Formula II and/or Formula III can be preparedwithout undue experimentation by conventional techniques well known tothose skilled in the art.

Salts and Formulations

It will be understood that, as used herein, references to the compoundsof structural Formula I, Formula II and/or Formula III are meant to alsoinclude the pharmaceutically acceptable salts, and also salts that arenot pharmaceutically acceptable when they are used as precursors to thefree compounds or their pharmaceutically acceptable salts or in othersynthetic manipulations. The term “pharmaceutically acceptable salt”refers to salts prepared from pharmaceutically acceptable non-toxicbases or acids including inorganic or organic bases and inorganic ororganic acids. Salts of basic compounds encompassed within the term“pharmaceutically acceptable salt” refer to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid. Representativesalts of basic compounds of the present invention include, but are notlimited to, the following: acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate,carbonate, chloride, clavulanate, citrate, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate, hexylresorcinate,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide and valerate. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof include, but are not limitedto, salts derived from inorganic bases including aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,mangamous, potassium, sodium, zinc, and the like. Particularly preferredare the ammonium, calcium, magnesium, potassium, and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, cyclic amines, andbasic ion-exchange resins, such as arginine, betaine, caffeine, choline,N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine, and thelike.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetyl,pivaloyl, benzoyl, and aminoacyl, can be employed. Included are thoseesters and acyl groups known in the art for modifying the solubility orhydrolysis characteristics for use as sustained-release or prodrugformulations.

Solvates, in particular hydrates, of the compounds of structural FormulaI, Formula II and/or Formula III are included in the present inventionas well.

According to an embodiment, the compounds of structural Formula I,Formula II and/or Formula III may be included in various formulationsfor use as medicaments.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the the partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavouring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

According to an embodiment, the cells are isolated using methods knownin the art for their preparation. For example, the cells may be isolatedfrom donors using mixtures of enzymes such as Collagenase I andCollagenase II, Thermolysin, non-clostridial neutral protease, or otherenzymes being used for such purpose. The isolated cells may then becultured under normal tissue culture conditions in standard tissueculture flasks.

According to an embodiment, the neurosensory precursor cells may betreated with a gem-difluorinated C-glycopeptide compound of generalformula I—preferably, the compound of Formula II, and most preferablythe compound of formula III in concentrations varying from about 0.01mg/ml to about 5 mg/ml; or from about 0.1 mg/ml to about 5 mg/ml; orfrom about 0.5 mg/ml to about 5 mg/ml; or from about 1 mg/ml to about 5mg/ml; or from about 3 mg/ml to about 5 mg/ml; or from about 0.01 mg/mlto about 3 mg/ml, or from about 0.1 mg/ml to about 3 mg/ml, or fromabout 0.5 mg/ml to about 3 mg/ml, or from about 1 mg/ml to about 3mg/ml, or from about 0.01 mg/ml to about 1 mg/ml; or from about 0.1mg/ml to about 1 mg/ml; or from about 0.5 mg/ml to about 1 mg/ml; orfrom about 0.01 mg/ml to about 0.5 mg/ml; or from about 0.1 mg/ml toabout 0.5 mg/ml; or from about 0.01 mg/ml to about 0.1 mg/ml; or about 3mg/ml. According to embodiments, the amounts above are considered to betherapeutically effective amounts for the purpose of the presentinventions.

According to another embodiment, the cells are contacted with thegem-difluorinated C-glycopeptide compound for a time sufficient toeffect improvements on cell viability and survival rate. According toembodiments, the time sufficient may be from about 12 hours to 120hours, or from about 12 hours to about 96 hours, or from about 12 hoursto about 72 hours, or from about 12 hours to about 48 hours, or fromabout 12 hours to about 24 hours, or about 120 hours, or about 96 hours,or about 72 hours, or about 48 hours, or about 24 hours, or about 12hours, or about 10 hours, or about 8 hours, or about 6 hours, or about 4hours, or about 2 hours, or about 1 hour. In embodiments, the whereinthe isolated neurosensory precursor cell is contacted with the compoundfor 1 hour, 55 mins, 50 mins, 45 mins, 40 mins, 35 mins, 30 mins, 25mins, 20 mins, 15 mins, 10 mins, 5 mins, 4 mins, 3 mins, 2 mins, 1 mins,45 secs, or 30 secs, or at least 1 hour, or at least 55 mins, or atleast 50 mins, or at least 45 mins, or at least 40 mins, or at least 35mins, or at least 30 mins, or at least 25 mins, or at least 20 mins, orat least 15 mins, or at least 10 mins, or at least 5 mins, or at least 4mins, or at least 3 mins, or at least 2 mins, or at least 1 mins, or atleast 45 secs, or at least 30 secs.

In another embodiment there is disclosed a cell preparation preparedaccording to the method of the present invention, in a pharmaceuticallyacceptable carrier. According to an embodiment, the cell preparation maybe used for the preparation of a medicament for a cell transplantation.According to another embodiment, the cell preparation may be used for acell transplantation.

In another embodiment, there is disclosed a method of transplantationcomprising transplanting a cell preparation of the present invention toa subject in need thereof. The subject may be a mammal, and preferably ahuman.

The present invention will be more readily understood by referring tothe following examples which are given to illustrate the inventionrather than to limit its scope.

EXAMPLE 1

To identify the key factors that inhibit NPC integration into diseasedtissue, an ex vivo tissue culture system has been developed to enablethe identification of factors that reduce and factors that enhance cellsurvival and functional integration (Yanai et al., 2015). The ex vivosystem mimics the subretinal space in a regulated environment thatincludes a neurosensory retinal explant placed on top of human embryonicstem cells (hESC) derived retinal pigment epithelium (RPE). NPCs (suchas human photoreceptor precursor cells; PPCs, Yanai et al., 2013) canthen be placed within the model in a more controlled environment. Thusthe role of adverse factors such as nutritional deficits and toxicmetabolites can be studied in isolation from other hostile effects suchas surgical trauma and immune rejection. It is hypothesized that toxicmetabolites, such as PGE2, are major adverse factors during tissuetransplantation in necrotic neurodegeneration of the retina.Furthermore, AAGP™ is selected as a potential protective agent, and itsability to prevent PGE2 toxic effects is examined. AAGP™ is a small,stable, synthetic analog of anti-freeze protein (AFP) which has beenshown to protect cells for example, against exposure to extremetemperatures and ultraviolet irradiation (US Patent publication No.US20090311203).

Now referring to FIGS. 1A and 1B, within the ex vivo system, ratneurosensory retinal explants are incubated upon human embryonic stemcells (hESC) derived retinal pigment epithelium (RPE). Neurosensoryretina was obtained from the S334ter-4 model of retinal degeneration(Chen et al, 1995) and cultured within the system for 10 days (fordetailed experimental design see Yanai et al., 2015). Rodent retinaltissue collection was carried out with approval of the Animal CareCommittee at the University of British Columbia and in accordance withthe Association for Research in Vision and Ophthalmology Statement forthe Use of Animals in Ophthalmic and Vision Research. Throughout thepresent study, AAGP™ was used at 4 mg/ml, after it was confirmed it wasnot toxic to PPCs at this concentration (unpublished data).

Firstly, the amount of PGE2 produced is determined within the ex vivosystem under normal culture conditions and after media is supplementedwith 4 mg/ml AAGP for the first 24 hours of co-culture. Threeequal-sized retinal quadrants, measuring ˜10 mm² each, and are analyzedfor each condition. Explant media are collected at the end of 10 daysand assessed for concentration of PGE2 by enzyme-linked immunosorbentassay (ELISA; R&D Systems). PGE2 induced reduction in metabolicactivity, contributing to cell death, is assessed in PPCs cultured inisolation using a Thiazolyl Blue Tetrazolium Bromide (MTT) assay(Sigma).

To determine whether AAGP™ inhibits COX-2 expression, ARPE-19 cells(Dunn et al., 1996) are treated with 17 ng/ml Interleukin 1 β (IL-1β;Sigma; Lukiw et al., 2006) for 8 hours and then added 5 mM ATP for 1hour to further induce cell stress (Sigma; Mehta et al., 2001). ARPE-19is a human retinal pigment epithelia (RPE) cell line spontaneouslyarising from a primary culture of RPE cells from a male donor. Thesecells have many morphological and some functional similarities withauthentic RPE. Experiments are conducted either in the presence orabsence of 4 mg/ml AAGP™. COX-2 expression is assessed using ReverseTranscription Quantitative Polymerase Chain Reaction (RT-qPCR) with theTaqMan® primer/probe system, Fast Advanced Master Mix and the ViiA™ 7Real Time PCR system (Applied Biosystems).

To determine whether AAGP™ improves PPC survival in the ex vivo system,PPC cell viability is assessed with and without pre-treating cell graftswith AAGP™ for 24 hours prior to inclusion within the ex vivo system.PPCs are labelled with 20 μM CellTrace™ Far Red DDAO-SE (LifeTechnologies). DDAO-SE is a fixable, far-red fluorescent tracer forlong-term cell labeling. The tracer is colorless and non-fluorescentuntil its acetate groups are cleaved by intracellular esterases to yieldhighly fluorescent products. DDAO-SE forms a strong covalent attachmentto primary amines on proteins and other biomolecules and is thereforenot likely to transfer to other types of cells in the co-culture. Ineach experiment (n=4), between 2 and 4 retinal explants are used foreach condition (‘technical repeats’). About 350,000 labeled PPCs areused in each technical repeat. After 10 days, the components of theco-culture system are enzymatically dissociated into single cellsuspensions and the number of viable PPCs is assessed byFluorescence-Activated Cell Sorting (FACS; Influx Sorter; BDBiosciences).

For statistical analyses an unpaired Student's t-test is performed. Pvalues of less than 0.05 are considered significant.

The results demonstrate that following 10 days of co-culture, theexplant medium contained ˜20 pg/ml of PGE2, and when AAGP™ is presentfor the first day, the amount of PGE2 decreased to ˜7.5 pg/ml (n=3;p<0.05; FIG. 2A).

A plausible reason for the reduced level of PGE2 in the presence ofAAGP™ is that COX-2 levels are downregulated by this compound. COX-2 isinduced by inflammatory stimuli and its expression is likely chronic inthe explant system, making it difficult to detect small changes inexpression levels. Therefore, COX-2 expression is assessed in culturedcells, responding to an acute stress, where the effect is maximized.COX-2 downregulation is confirmed in an ARPE-19 cell stress assay usingIL-1β followed by ATP. COX-2 expression is evident in stressed cells butthis expression declined by at least 13.3±4.5 fold, to negligiblelevels, in the presence of AAGP™ (n=4; FIG. 2B). To examine whether PGE2is toxic to cells, PPCs are cultured for 48 hours in retinaldifferentiation medium supplemented with increasing amounts of PGE2 (upto 50 μM) and analyzed cells survival by the MTT assay (n=4). Cellsurvival is reduced by up to 44% (FIG. 2C), confirming PGE2 toxicity.

Finally, the viability of PPCs in the ex vivo system is tested.Untreated PPCs or PPCs pre-treated for 24 hours with 4 mg/ml AAGP™ arelabelled with a fluorescent live cell tracer and ˜350,000 PPCs areplaced in-between the explant and RPE. Ten days later, the co-culturedcomponents were dissociated into single cells and viable PPCs (labeledred) were separated by Fluorescence activated cell sorting (FACS, FIG.3). The proportion of live cells remaining after 10 days of co-cultureis calculated. An almost 3-fold increase in average cell viability isobtained when PPCs are pre-treated with AAGP™ for 24 hours before“transplantation” (49% vs. 18%; p<0.05).

Altogether the results presented in this study indicate that NPCs, suchas PPCs, transplanted into neurological tissue may, in part, die as aresult from exposure to PGE2 released from host necrotic tissue, suchnecrosis is a cause of retinal degenerations such as retinal detachment.Targeting toxic by-products such as PGE2 therefore appears tosurprisingly and unexpectedly be a valid option to improve survival oftransplanted precursor cells. The data presented here suggests thatAAGP™ may have a role in inhibiting PGE2 production in necrotic tissueex vivo.

The ex vivo system presented herein appears to be an appropriatescreening method to identify valid therapeutics to move into more laborintensive in vivo studies. These results also suggest that otherinhibitors of COX2, such as non-steroidal anti-inflammatory drugs, maylikewise enhance survival of transplanted NPCs during celltransplantation experiments.

While preferred embodiments have been described above and illustrated inthe accompanying drawings, it will be evident to those skilled in theart that modifications may be made without departing from thisdisclosure. Such modifications are considered as possible variantscomprised in the scope of the disclosure.

REFERENCES

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1. A method for protecting isolated neurosensory precursor cells fromprostaglandin E2 toxicity comprising the step of: a) contacting anisolated neurosensory precursor cell with a gem-difluorinatedC-glycopeptide compound of general formula I, or a pharmaceuticallyacceptable base, addition salt with an acid, hydrate or solvate thereof,and then washing the isolated neurosensory cells to remove the compound:

in which: N is an integer between 1 and 5, R⁴═H, AA₁, or AA₁-AA₂, R⁵═OH,AA₁, or AA₁-AA₂, AA₁ and AA₂ independently represent amino acids with anon-polar side chain and R¹, R², R³ are independent groups in which twoof R¹, R² and R³ are selected from H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂or CH(CH₃)CH₂CH₃ and the remaining R¹, R², R³ is

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′═H, OR, N₃, NR′R″, or SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl oracetate group, R′, R″ independently=H, alkyl, allyl, benzyl, tosylategroup, C(═O)-alkyl or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ is H,CH₃, CH₂OH, CH₂-glycoside group or CH₂—OGP in which GP is a protectorgroup selected from alkyl, benzyl, trimethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,R⁷═OH, OGP′, NH₂, N₃, NHGP′ or NGP′GP″ in which GP′ and GP″ areindependently selected from alkyl, benzyl, trimethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group, R⁸is a hydrogen atom H or a free or protected alcohol function, and ifR¹═R²═H, CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃ then

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′═H, OR, N₃, NR′R″, or SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, oracetate group, R′, R″ independently=H, alkyl, allyl, benzyl, tosylategroup, C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ isH, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is aprotector group selected from alkyl, benzyl, trimethylsilyl,tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ areindependently selected from alkyl, benzyl, trimethylsilyl,tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group, R⁸ isa hydrogen atom H or a free or protected alcohol function, if R¹═R³═H,CH₃, CH₂Ph, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃ then

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′═H, OR, N₃, NR′R″, or SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, oracetate group, R′, R″ independently=H, alkyl, allyl, benzyl, tosylategroup, C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ isH, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is aprotector group selected from alkyl, benzyl, trimethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ areindependently selected from alkyl, benzyl, trimethylsilyl,tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group, R⁸ isa hydrogen atom H or a free or protected alcohol function, if R²═R³═H,CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, or CH(CH₃)CH₂CH₃ then

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′H, OR, N₃, NR′R″, or SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, oracetate group, R′, R″ independently=H, alkyl, allyl, benzyl, tosylategroup, C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ isH, CH₃, CH₂OH, CH₂-glycoside group, or CH₂—OGP in which GP is aprotector group selected from alkyl, benzyl, trimethylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group,R⁷═OH, OGP′, NH₂, N₃, NHGP′, or NGP′GP″ in which GP′ and GP″ areindependently selected from alkyl, benzyl, trimethylsilyl,tertbutyldimethylsilyl, tert-butyldiphenylsilyl, or acetate group, R⁸ isa hydrogen atom H or a free or protected alcohol function b)transplanting the treated isolated neurosensory precursor cells of stepa) in a subject in need thereof, wherein said compound protects saidisolated neurosensory precursor cell from prostaglandin E2 toxicity andwherein the method comprises no step where said isolated neurosensoryprecursor cells are cryopreserved.
 2. The method of claim 1, wherein thecompound of formula I is a compound of formula II:

in which: N is an integer between 1 and 5, and R¹, R², R³ areindependent groups in which two of R¹, R² and R³ are selected from H,CH₃ and the remaining R¹, R² and R³ is

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′═H, OR, N₃, NR′R″ or SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, oracetate group, R′, R″ independently=H, alkyl, allyl, benzyl, tosylategroup, C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ isselected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a protector groupselected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group, R⁷═OH, OGP′, NH₂, N₃, NHGP′,NGP′GP″ in which GP′ and GP″ are independently selected from alkyl,benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilylor acetate group, R⁸ is a hydrogen atom H or a free or protected alcoholfunction, and if R¹═R²═H or CH₃, then

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′═H, OR, N₃, NR′R″, or SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, oracetate group, R′, R″ independently=H, alkyl, allyl, benzyl, tosylategroup, C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ isselected from H, CH₃, CH₂OH, CH₂—OGP in which GP is a protector groupselected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group, R⁷═OH, OGP′, NH₂, N₃, NHGP′,NGP′GP″ in which GP′ and GP″ are independently selected from alkyl,benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group, R⁸ is a hydrogen atom H or afree or protected alcohol function, if R¹═R³═H or CH₃, then

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′═H, OR, N₃, NR′R″, SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, oracetate group, R′, R″ independently=H, alkyl, allyl, Bn, tosylate,C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ is selectedfrom H, CH₃, CH₂OH, or CH₂—OGP in which GP is a protector group selectedfrom alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group, R⁷═OH, OGP′, NH₂, N₃, NHGP′,or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl,benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group, R⁸ is a hydrogen atom H or afree or protected alcohol function, if R²═R³═H or CH₃, then

in which: n is an integer between 3 and 4, Y, Y′ are independent groupsin which Y, Y′H, OR, N₃, NR′R″, or SR′″, where R═H, benzyl,trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, oracetate group, R′, R″ independently=H, alkyl, allyl, benzyl, tosylategroup, C(═O)-alkyl, or C(═O)-Bn, R′″═H, alkyl, or acetate group, R⁶ isselected from H, CH₃, CH₂OH, or CH₂—OGP in which GP is a protector groupselected from alkyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group, R⁷═OH, OGP′, NH₂, N₃, NHGP′,or NGP′GP″ in which GP′ and GP″ are independently selected from alkyl,benzyl, trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, or acetate group, R⁸ is a hydrogen atom or afree or protected alcohol function.
 3. The method of claim 1, whereinsaid compound of formula I is a compound of formula III:


4. The method of claim 1, wherein the isolated neurosensory precursorcell is contacted with the compound for at least 1 hour.
 5. The methodof claim 1, wherein concentration of the compound is from about 1 mg/mlto about 5 mg/ml.
 6. The method of claim 5, wherein concentration ofsaid compound is from about 1 mg/ml to about 3 mg/ml, or from about 3mg/ml to about 5 mg/ml.
 7. The method of claim 1, wherein saidneurosensory precursor cell is a photoreceptor precursor cell.
 8. Anisolated neurosensory precursor cell prepared according to the method ofany one of claim
 1. 9. The method of claim 1, wherein said subject isreceiving an immunosuppressant drug.
 10. The method of claim 9, whereinthe immunosuppressant drug is daclizumab, sirolimus, tacrolimus,cyclosporine, or a combination thereof.
 11. The method of claim 1,wherein said subject is a human subject.
 12. The method of claim 1,wherein said method is for treating a retinal degenerative disease. 13.The method of claim 12, where said retinal degenerative disease isage-related macular degeneration (AMD), retinitis pigmentosa (RP),retinal vasculitis, or sarcoidosis.